This Article Abstract Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Zurrida, S. Articles by Veronesi, U. Search for Related Content PubMed PubMed Citation Articles by Zurrida, S. Articles by Veronesi, U. Related Collections Radiation Therapy Surgery

Axillary Radiotherapy Instead of Axillary Dissection: A Randomized Trial

From the Departments of Senology (SZ, VG, AL, BB, AA, GV, UV) and Radiotherapy (RO) and the Division of Epidemiology and Biostatistics (IG), European Institute of Oncology, Milan, Italy.

Correspondence: Address correspondence and reprints requests to: Stefano Zurrida, MD, Istituto Europeo di Oncologia, Via G. Ripamonti, 435, 20141 Milano, Italy; Fax: 39-2-57489210; E-mail: francesca.morelli{at}ieo.it

	ABSTRACT

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION APPENDIX REFERENCES

 
Background: Surgical dissection of the axilla is a standard part of the treatment of breast cancer but, by itself, does not improve prognosis; furthermore, most patients with small-sized breast cancer and a clinically uninvolved axilla never develop axillary metastases. We evaluated disease-free and overall survival in patients with early breast cancer treated by breast-conservation surgery without dissection of axillary lymph nodes, receiving or not receiving axillary radiotherapy (RT).

Methods: From 1995 to 1998, 435 patients older than 45 years with breast cancer up to 1.2 cm were randomized, 214 to breast conservation without axillary treatment and 221 to breast conservation plus axillary RT.

Results: After a follow-up of 28 to 68 months (median, 42 months), two women (1%) in the no axillary treatment group and one (.5%) in the axillary RT group developed axillary metastases. Rates of distant metastases and local treatment failure were also very low, and 5-year overall survival was 99%.

Conclusions: After a mean of 46 months of follow-up, our results indicate that axillary dissection can be safely avoided in patients with very small invasive carcinomas and a clinically negative axilla. Whether axillary RT should be added can be assessed only by longer follow-up.

Key Words: Breast cancer • Axillary radiotherapy • Lymph nodes • Metastases • Randomized trial

	INTRODUCTION

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION APPENDIX REFERENCES

 
The major National Surgical Adjuvant Breast and Bowel Project-06 study showed that not performing axillary dissection immediately does not affect the prognosis for clinically node-negative breast cancer treated by total mastectomy.¹ A more recent study demonstrated that dissection of the internal mammary nodes at the time of mastectomy does not improve the prognosis.² Thus, regional lymph node dissection does not seem important, in itself, for survival in patients with a clinically clear axilla, although the indication to dissect an involved axilla remains.

In line with these findings, axillary dissection has been abandoned in patients with in situ carcinomas, and many authors propose that it should also be abandoned in patients with intraductal carcinoma and microinvasive foci and in those older than 65 years, provided that follow-up is attentive.^3,4

Today, breast cancers are diagnosed at an increasingly early stage, and the axilla is often found healthy on surgical dissection. In fact, occult axillary metastases are present in only 10% to 20% of patients with very small breast cancer.⁵ These percentages increase with tumor size⁶ and also as more exhaustive methods of histological examination are used in the context of sentinel node biopsy.⁷ However, most patients with a clinically uninvolved axilla never develop axillary metastases.⁸

For these reasons we considered it important to investigate the effect of foregoing axillary dissection in patients with early breast cancer and no palpable axillary nodes. Because we expected that a number of such patients might develop axillary metastases during follow-up, we decided to treat half with axillary radiotherapy (RT), thereby evaluating the ability of this treatment to reduce the rate of overt axillary metastases. RT can destroy cancer cells in the axilla without major side effects.⁹ Furthermore, the 20-year follow-up of a randomized trial indicated that axillary RT may be an acceptable substitute for axillary dissection.¹⁰ Under the auspices of the Italian Oncological Senology Group, we initiated a multicenter randomized trial in 1995 to investigate the role of no axillary treatment versus axillary RT in breast cancer.

	PATIENTS AND METHODS

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION APPENDIX REFERENCES

 
Women aged 45 years or older with unifocal breast cancer, maximal diameter 1.2 cm (determined by mammography or ultrasonography), and no palpable axillary nodes were eligible. Noninvasive carcinoma or a history of malignant disease were exclusion criteria. Patients gave written consent after the potential risks and benefits of this nonstandard axillary treatment had been discussed with them. Enrolled patients were randomized either to no axillary treatment or to axillary RT by contacting the randomization center of the Division of Epidemiology, European Institute of Oncology. Patients were recruited from January 1995 to July 1998.

The treatment given to the breast was wide resection or quadrantectomy. For nonpalpable lesions, the removed specimen was x-rayed to verify complete tumor removal.

All patients received x-ray RT to the breast given as two opposed tangential fields, nonparallel to avoid posterior beam divergence and to minimize lung and heart (for the left breast) irradiation. The central lung distance never exceeded 2 cm.

Patients with positive estrogen receptors were prescribed tamoxifen for 5 years (321; 73.8%). Those with negative estrogen receptors, high tumor grade (grade 3), and high proliferation rate (Ki-67 >20%) received cyclophosphamide, methotrexate, and fluorouracil for 6 months (30; 6.9%). The remaining 84 patients (19.3%) received no adjuvant therapy.

All patients were examined quarterly and were given mammography, chest x-ray, liver ultrasound, and bone scan annually. Any enlarged axillary node that developed during follow-up was treated by complete axillary dissection.

The primary aim was to compare the two arms of the study (no axillary treatment vs. axillary RT) in terms of the incidence of axillary metastases. We assumed that over 8 years of follow-up, 15% of the patients who received no axillary control would develop axillary metastases, whereas axillary RT would reduce this figure to 3%.

	RESULTS

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION APPENDIX REFERENCES

 
Over the study period, 435 patients were recruited: 221 were randomized to axillary RT and 214 to no axillary treatment. The two groups were closely comparable in main characteristics (tumor size distribution, histology, tumor grade, hormonal receptor status, and proliferative index; Table 1). In 40 patients (20 from each group), pathologic examination showed that the tumor diameter slightly exceeded the 1.2 cm determined during the operation at randomization.

Three patients developed breast cancer recurrence (all in the no axillary treatment arm), and six developed contralateral carcinoma (four in the axillary RT arm and two in the no axillary treatment arm). Seven patients developed distant metastases, six in the axillary RT arm and one in the no axillary treatment group.

In one patient, only axillary RT caused major side effects: grade 3 upper-arm paresthesia, which persisted for 6 months. Three patients (.7%) were lost to follow-up. Three patients developed other primary tumors, two (endometrial carcinoma and brain glioblastoma) in the axillary RT arm and one (bladder carcinoma) in the no axillary treatment arm. There have been four deaths, all among patients who received axillary RT; two died of distant metastases of breast carcinoma and two of other causes.

	DISCUSSION

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION APPENDIX REFERENCES

 
The most striking finding of this study is the exceptionally low rate of axillary metastases in both groups during the 5-year follow-up. Only 1 patient of 221 in the axillary RT group and 2 patients of 214 in the no axillary treatment group developed clinically overt axillary metastases. Perhaps the low rate in the axillary RT group can be attributed to the sterilizing effect of RT. However, this cannot explain the similarly low rate in the no axillary treatment group.

In a series of 458 consecutive patients treated at European Institute of Oncology and presented at the Society of Surgical Oncology symposium⁷ in 2000, the average age and tumor size were similar to those in this series, and axillary involvement was present at histological examination in 112 (24.45%) of 458. Applying this proportion to this study, 52 of the 214 patients assigned to the no axillary RT group would be expected to have microscopic axillary node involvement and should therefore develop axillary metastases during follow-up. Perhaps additional cases will appear subsequently. However, it is also possible that the occult cancer cells in the lymph nodes will never progress to overt axillary metastases in most cases. We speculate that the undamaged immunocompetent tissue in the axilla may keep micrometastases silent and promote long-term disease-free survival.

Ten-year results of the randomized trial by Fisher et al.¹ on women with primary operable breast cancer showed that for patients who underwent total mastectomy alone (without axillary dissection and without radiation), the highest risk of axillary node involvement was concentrated in the first 24 months after surgery; the median time from mastectomy to a delayed axillary dissection was 14.7 months (range, 3–112.6 months). Another study, by Greco et al.,⁴ on patients with breast cancer of 3 cm or smaller, showed that the median axillary-free elapsed time was 30.6 months (range, 6–72 months) and that the rate of axillary metastases increased progressively with the size of the primary tumor. In both these studies, the rate of axillary involvement was less than expected. These data support our hypothesis that not all the metastatic cells in lymph nodes progress to evident metastases and that immunocompetent tissue not removed from the axilla could have a role in the long-term control of the disease.

As regards the role of axillary RT in preventing the appearance of axillary metastases, the very low incidence of this event makes evaluation impossible. The patients are being observed with quarterly clinical and ultrasound examination of the axilla, and the data will be analyzed again after 2 years. Among the 221 patients who received axillary irradiation, only one had grade 3 side effects: transient arm paresthesia, which persisted for 6 months. This very low rate of complications is probably because the total dose of 50 Gy was given over 5 weeks, the irradiated volume was limited (the supraclavicular region was excluded), and previous axillary dissection had not been performed.

Because old data indicated that the recurrence rate in the axilla after standard breast irradiation was lower than if irradiation was not given,¹ it has been considered that part of the axilla is irradiated, even though the axilla was not expressly included in the irradiation volume. Simulation film-based analyses have also shown that the first axillary level is often included in standard tangential fields.^11,12 Our more recent analyses (manuscript in preparation, M. C. Leonardi, January 2001), based on computed tomography and three-dimensional reconstruction, indicate that axillary irradiation through tangential breast fields is not significant. The first level, in fact, is only partially included and, more importantly, does not receive clinically significant doses. We take the view, therefore, that therapeutic doses are rarely delivered to the first axillary level nodes with the standard tangential technique. Specific treatment planning and beam arrangement are required if adequate coverage to the axilla is required. We suggest that the reduction in axillary recurrences in breast irradiated patients is due to the sterilization of skip metastases, as proposed by Krasin et al.¹³

We comment, finally, on the importance of these findings in relation to sentinel node biopsy. This technique is able to accurately stage the axilla, particularly in small breast cancers.¹⁴ However, in very small cancers, the likelihood of metastases in the axilla is so low that even the use of sentinel node biopsy has been questioned.^3,5,8 When axillary dissection is not performed, the rate of axillary recurrence seems to be lower than expected, so one suspects that micrometastases and even some macrometastases detected by sentinel node biopsy or axillary dissection will never became clinically evident. The clinical significance of the high rate of micrometastases detected by extensive histological examination of the sentinel node remains to be determined by future studies.

To conclude, the findings of this randomized trial are that the rate of axillary metastases appearing in women treated by breast conservation without axillary dissection is lower than expected and that there is at present no difference between the group given axillary RT and that which received no axillary treatment. Perhaps longer follow-up will reveal a difference and suggest whether axillary RT can significantly reduce the long-term risk of overt axillary involvement. We also found that distant metastases are rare in this series, with overall actuarial survival at 5 years close to 99%. It seems, therefore, that axillary dissection can be safely avoided in women with very small invasive carcinomas (diameter <1.2 cm) and a clinically negative axilla.

	APPENDIX

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION APPENDIX REFERENCES

 
GrISO (Italian Oncological Senology Group; Umberto Veronesi, MD, Coordinator; Alberto Luini, MD, Secretary; and Patrick Maisonneuve, Statistician) consists of Viviana Galimberti, MD, Roberto Orecchia, MD, and Franco Nolè, MD (Milan); Giuseppe D’Aiuto, MD, Massimo Rinaldo, MD, and Pasquale Frezza, MD (Napoli); Luigi Cataliotti, MD, Lorenzo Orzalesi, MD, Roberta Simoncini, MD, and Paolo Pacini, MD (Firenze); Franco Lo Sardo, MD, Piero Liotta, MD, and Biagio Agostara, MD (Palermo); Piero Sismondi, MD, Maria Piero Mano, MD, and Rita Bordon, MD (Torino 1); Napoleone Massaioli, MD, Claudio Coluccia, MD, Marilena Sacco, MD, and Michela Donadio, MD (Torino 2); Angelo Recalcati, MD, Maria Limonta, MD, and Maria Colombo, MD (Lecco); Stefano Modena, MD, Anna Acerbi, MD, Barbara Carrara, MD, and Mario Romano, MD (Verona); Rocco Paolucci, MD, Pierluigi Piccolo, MD, Marco Fumagalli, MD, and Giuseppe Finzi, MD (Parma); Daniela Terribile, MD, Cinzia Locastro, MD, Luigia Nardone, MD, and Gianpiero Ausili, MD (Roma-Gemelli); and Antonio Rulli, MD, Annarita Vento, MD, and Paolo Latini, MD (Perugia).

	Acknowledgments

 
Supported by the Italian Association for Cancer Research (AIRC). The authors thank Don Ward for help with the English.

	Footnotes

 
Presented at the 54th Annual Meeting of the Society of Surgical Oncology, Washington, DC, March 15–18, 2001.

Received for publication March 16, 2001. Accepted for publication September 26, 2001.

	REFERENCES

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION APPENDIX REFERENCES

 

1. Fisher B, Redmond C, Fisher ER, et al. Ten-year results of a randomized trial comparing radical mastectomy and total mastectomy with or without radiation. N Engl J Med 1985; 312: 674–81.[Abstract]
2. Veronesi U, Marubini E, Mariani L, Valagussa P, Zucali R. The dissection of internal mammary nodes does not improve the survival of breast cancer patients. 30-year results of a randomized trial. Eur J Cancer 1999; 35: 1320–5.
3. Silverstein MJ, Gierson ED, Waisman JR, et al. Axillary lymph node dissection for T1a breast carcinomas. Is it indicated? Cancer 1994; 73: 664–7.
4. Greco M, Agresti R, Cascinelli N, et al. Breast cancer patients treated without axillary surgery. Clinical implications and biologic analysis. Ann Surg 2000; 232: 1–7.[CrossRef][Medline]
5. Cady B, Stone MD, Schuler JG, Thakur R, Wanner MA, Lavin PT. The new era in breast cancer. Invasion, size, and nodal status involvement dramatically decreasing as result of mammographic screening. Arch Surg 1996; 131: 301–8.[Abstract/Free Full Text]
6. Zurrida S, Morabito A, Galimberti V, et al. Importance of the level of axillary involvement in relation to traditional variables in the prognosis of breast cancer. Int J Oncol 1999; 15: 475–80.[Medline]
7. Zurrida S, Mazzarol G, Galimberti V, et al. The problem of the accuracy of intraoperative examination of axillary sentinel nodes in breast cancer. Ann Surg Oncol 2001; 8: 817–20.[Abstract/Free Full Text]
8. Lee AKC, Loda M, Mackarem G, et al. Lymph node negative invasive breast carcinoma 1 centimeter or less in size (T1a,bN0M0): clinicopathologic features and outcome. Cancer 1997; 79: 761–71.[CrossRef][Medline]
9. Hoebers FJP, Borger JH, Hart AAM, Peterse JL, Rutgers EJT, Lebesque JV. Primary axillary radiotherapy as axillary treatment in breast-conserving therapy for patients with breast carcinoma and clinically negative axillary lymph nodes. Cancer 2000; 88: 1633–42.[CrossRef][Medline]
10. Johansen H, Kaae S, Schiodt T. Simple mastectomy with postoperative irradiation versus extended radical mastectomy in breast cancer. A twenty-five-year follow-up of a randomized trial. Acta Oncol 1990; 29: 709–15.[Medline]
11. Recht A, Houlihan M. Axillary lymph nodes and breast cancer. Cancer 1995; 76: 1491–512.[CrossRef][Medline]
12. Wong J, Recht A, Beard C, et al. Treatment outcome after tangenttial irradiation therapy without axillary dissection in patients with early-stage breast cancer and clinically negative axillary nodes. Int J Radiat Oncol Biol Phys 1997; 39: 915–20.[CrossRef][Medline]
13. Krasin M, McCall A, King S, Olsen M, Imami B. Evaluation of a standard breast tangent technique: a dose-volume analysis of tangential irradiation using three dimensional tools. Int J Radiat Oncol Biol Phys 2000; 47: 327–33.[CrossRef][Medline]
14. Veronesi U, Paganelli G, Viale G, et al. Sentinel lymph node biopsy and axillary dissection in breast cancer: results in a large series. J Natl Cancer Inst 1999; 91: 368–73.[Abstract/Free Full Text]

This article has been cited by other articles:

				B. Cady Regional Lymph Node Metastases; a Singular Manifestation of the Process of Clinical Metastases in Cancer: Contemporary Animal Research and Clinical Reports Suggest Unifying Concepts Ann. Surg. Oncol., June 1, 2007; 14(6): 1790 - 1800. [Abstract] [Full Text] [PDF]

				U. Veronesi, R. Orecchia, S. Zurrida, V. Galimberti, A. Luini, P. Veronesi, G. Gatti, G. D'Aiuto, L. Cataliotti, R. Paolucci, et al. Avoiding axillary dissection in breast cancer surgery: a randomized trial to assess the role of axillary radiotherapy Ann. Onc., March 1, 2005; 16(3): 383 - 388. [Abstract] [Full Text] [PDF]

				A. Luini, G. Gatti, B. Ballardini, S. Zurrida, V. Galimberti, P. Veronesi, A. R. Vento, S. Monti, G. Viale, G. Paganelli, et al. Development of axillary surgery in breast cancer Ann. Onc., February 1, 2005; 16(2): 259 - 262. [Abstract] [Full Text] [PDF]

				N. P. Schneidereit, N. Davis, M. Mackinnon, C. H. Speers, P. T. Truong, and I. A. Olivotto T1a Breast Carcinoma and the Role of Axillary Dissection Arch Surg, August 1, 2003; 138(8): 832 - 837. [Abstract] [Full Text] [PDF]

				B. D. Badgwell, S. P. Povoski, S. F. Abdessalam, D. C. Young, W. B. Farrar, M. J. Walker, L. D. Yee, E. E. Zervos, W. E. Carson III, and W. E. Burak Jr Patterns of Recurrence After Sentinel Lymph Node Biopsy for Breast Cancer Ann. Surg. Oncol., May 1, 2003; 10(4): 376 - 380. [Abstract] [Full Text] [PDF]

				J. S. Wong and J. R. Harris Can Specific Axillary Radiotherapy Be Omitted in Undissected, Clinically Node-Negative Patients Who Undergo Breast-Conserving Therapy? Ann. Surg. Oncol., March 1, 2002; 9(2): 117 - 119. [Full Text] [PDF]

This Article Abstract Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Zurrida, S. Articles by Veronesi, U. Search for Related Content PubMed PubMed Citation Articles by Zurrida, S. Articles by Veronesi, U. Related Collections Radiation Therapy Surgery